Viviana Fridman

Expression Pattern of Metalloproteinases and Tissue Inhibitors of Matrix-Metalloproteinases in Cycling Human Endometrium

Abstract The cyclic growth, differentiation, and cell death of endometrium represents the most dynamic example of steroid-driven tissue turnover in human adults. Key effectors in these processes—matrix metalloproteinases (MMPs) and their specific inhibitors (TIMPs)—are regulated by ovarian steroids and, locally, by cytokines. We used reverse transcription-polymerase chain reaction to evaluate the expression of both transcriptionally regulated molecules such as estrogen receptor-α, progesterone receptor, and prolactin and a large array of MMPs and TIMPs (MMP-1, -2, -3, -7, -8, -9, -11, -12, -19, -26, MT1-MMP, MT2-MMP, MT3-MMP, TIMP-1, -2, -3). Altogether, three distinct patterns of MMP and two patterns of TIMP expression were detected in cycling endometrium: 1) MMPs restricted to the menstrual period (MMPs-1, -3, -8, -9, -12); 2) MMPs and TIMPs expressed throughout the cycle (MMP-2, MT1-MMP, MT2-MMP, MMP-19, TIMP-1, and TIMP-2); 3) MMPs predominantly expressed during the proliferative phase (MMP-7, MMP-11, MMP-26, and MT3-MMP); and 4) TIMP-3, which, contrary to the other TIMPs, shows significant modulations, with maximum expression during the late secretory and menstrual phases. These specific patterns of MMP expression associated with each phase of the cycle may point to specific roles in the processes of menstruation, housekeeping activities, angiogenesis, tissue growth, and extracellular matrix remodeling.

The combined immunodetection of AP-2α and YY1 transcription factors is associated with ERBB2 gene overexpression in primary breast tumors

IntroductionOverexpression of the ERBB2 oncogene is observed in about 20% of human breast tumors and is the consequence of increased transcription rates frequently associated with gene amplification. Several studies have shown a link between activator protein 2 (AP-2) transcription factors and ERBB2 gene expression in breast cancer cell lines. Moreover, the Yin Yang 1 (YY1) transcription factor has been shown to stimulate AP-2 transcriptional activity on the ERBB2 promoter in vitro. In this report, we examined the relationships between ERBB2, AP-2α, and YY1 both in breast cancer tissue specimens and in a mammary cancer cell line.MethodsERBB2, AP-2α, and YY1 protein levels were analyzed by immunohistochemistry in a panel of 55 primary breast tumors. ERBB2 gene amplification status was determined by fluorescent in situ hybridization. Correlations were evaluated by a χ2 test at a p value of less than 0.05. The functional role of AP-2α and YY1 on ERBB2 gene expression was analyzed by small interfering RNA (siRNA) transfection in the BT-474 mammary cancer cell line followed by real-time reverse transcription-polymerase chain reaction and Western blotting.ResultsWe observed a statistically significant correlation between ERBB2 and AP-2α levels in the tumors (p < 0.01). Moreover, associations were found between ERBB2 protein level and the combined high expression of AP-2α and YY1 (p < 0.02) as well as between the expression of AP-2α and YY1 (p < 0.001). Furthermore, the levels of both AP-2α and YY1 proteins were inversely correlated to ERBB2 gene amplification status in the tumors (p < 0.01). Transfection of siRNAs targeting AP-2α and AP-2γ mRNAs in the BT-474 breast cancer cell line repressed the expression of the endogenous ERBB2 gene at both the mRNA and protein levels. Moreover, the additional transfection of an siRNA directed against the YY1 transcript further reduced the ERBB2 protein level, suggesting that AP-2 and YY1 transcription factors cooperate to stimulate the transcription of the ERBB2 gene.ConclusionThis study highlights the role of both AP-2α and YY1 transcription factors in ERBB2 oncogene overexpression in breast tumors. Our results also suggest that high ERBB2 expression may result either from gene amplification or from increased transcription factor levels.

Contribution of whole-body 18FDG PET imagining in the management of cervical cancer

OBJECTIVE The objective of this study was to assess the contribution of [(18)F]fluoro-2-deoxy-D-glucose positron emission tomography ((18)FDG PET) imaging in the management of cervical cancer. METHODS Fully corrected whole-body PET was performed in 60 patients (pts) with proven cervical cancer. In pretreatment staging, 22 pts underwent PET in addition to routine protocol including International Federation of Obstetrics and Gynecology (FIGO) staging and pelvic magnetic resonance imaging (MRI). Eighteen of them had pelvic lymphadenectomy. After treatment, PET was performed in 38 pts routinely followed up by clinical and radiological examinations. Results of PET and routine protocols were compared to final diagnoses, including histological findings in 31 pts and clinical outcomes in the other cases. Median follow-up time was 12 +/- 7.3 months. RESULTS In all but 2 patients (FIGO stage IA), both PET and MRI detected the primary tumor. In 6 pts, MRI alone noted loco-regional tumor spread but PET localized 9 unsuspected extrapelvic nodal sites (6 para-aortic, 2 mediastinal, and 1 supra-clavicular). However, PET missed 8 microscopic pelvic nodal metastases. In 18% of the patients, PET staging significantly influenced the treatment choices. In follow-up, PET accurately diagnosed a recurrent disease in 13 pts with falsely negative or equivocal conventional imaging (CI). Ten patients with a negative PET were still in complete remission after a minimal follow-up time of 12 months. Overall, the agreement of PET with final diagnosis was significantly better than that of routine protocol (P < 0.05). CONCLUSIONS Whole-body (18)FDG PET appears useful in the management of cervical cancer, in particular for staging extrapelvic metastases or optimally detecting a recurrence. MRI is better indicated for evaluating the loco-regional status of the disease.